In the first funding period, we compared the risk of PD in relatives of 221 PD patients with age at onset (AAO) <50 to relatives of 266 PD patients with AAO >50 and 409 controls. The magnitude of increased risk of relatives of PD cases vs. controls was similar in early-onset cases (RR: 2.9, 95%C1: 1.6-5.0) and late onset cases (RR: 2.7, 95%CI: 1.6-4.4). However in families of early-onset cases, the degree of increased risk was much greater in siblings (RR: 7.9, 95%C1: 2.5-25.5) than in parents (RR: 1.7, 95% CI: 0.9-3.3), consistent with an autosomal recessive contribution to inheritance. In late-onset families, risk was elevated in both parents and siblings, inconsistent with a recessive model. Mutations in the parkin gene have emerged as the most important causative or risk-raising factor in early-onset PD. In this second competitive renewal application, we have redesigned our study to make optimal use of 300 early onset cases already recruited at the Columbia site (200 not yet screened for parkin mutations) and the 40 PD cases with parkin mutations we have already identified. We will join with investigators at 7 other sites who will contribute an additional 600 cases with age of onset <50 and 21 identified parkin families to form a US Parkin Consortium. Our first aim is the expansion of 125 PD cases that carry parkin mutations to include 1st and 2nd degree relatives. We will determine whether the risk of psychiatric and cognitive manifestations in asymptomatic gene carriers who do not meet criteria for PD is higher than in asymptomatic non-gene carriers. Identification of a parkin carrier phenotype will provide clues to etiopathogenesis and may define the appropriate time for early therapeutic intervention. Our second aim is to define the distribution of age specific penetrance in 100 of the 125 families who were recruited solely be age of onset, so as not to bias these estimates upward by inclusion of "high risk" families recruited because they are multiplex. We will compare differences in age specific penetrance by allelotype (heterozygous vs. homozygous or compound heterozygous). The results of this study will clarify the role of parkin in genetic susceptibility and foster the development of genetic testing guidelines. The consistent finding that at least 30 percent of PD patients with parkin mutations are heterozygotes, despite that fact that inheritance was initially described as recessive, and new availability of commercial testing make this study both critical and timely. [unreadable] [unreadable]